Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated apolipoprotein (apo) B-100 is a common abnormality in insulin-resistant subjects with obesity and type 2 diabetes mellitus that increases risk of cardiovascular disease. ApoB-100 metabolism is complex. Kinetic studies using stable isotope tracer have provided useful mechanistic insight into its therapeutic regulation. Dysregulation of apoB-100 metabolism is integral to dyslipidaemia in the metabolic syndrome (MetS). This is dynamically related to a combination of overproduction of very-low density lipoprotein apoB-100 and decreased catabolism of apoB-containing particles, with accelerated catabolism of high-density lipoprotein (HDL) particles. These abnormalities may be consequent on a global effect of insulin resistance and accumulation of visceral and liver fat. Several therapeutic interventions, such as weight loss, physical exercise, statins, fibrates, fish oils and cholesteryl ester transfer protein inhibitors can correct apoB-100 metabolism in MetS. This encapsulates several kinetic mechanisms of action, including decreased secretion of apoB-100, increased catabolism of apoB-100 and delayed catabolism of HDL particles. Other agents, including cholesterol absorption inhibitors, niacins, and endocannabinoid-1 receptor blockers, have also been shown to improve plasma lipid and lipoprotein abnormalities in insulin resistance; their mechanisms of action require further investigation in MetS. The complementary mechanisms of action of different therapies support the use of combination regimens to treat dyslipoproteinaemia in MetS, including type 2 diabetes. Tracer methodology is a powerful tool to evaluate established and new lipid-regulating therapies.
 ...
PMID:Therapeutic regulation of apoB100 metabolism in insulin resistance in vivo. 1949 Sep 28

Patients with type 2 diabetes feature important modification of both low density lipoprotein (LDL) and high density lipoprotein particles which are likely to play an important role in the development of atherosclerosis. Although plasma LDL cholesterol level is usually normal in type 2 diabetic patients, LDLs show a significant increase in their plasma residence time which may promote cholesterol deposition in the arterial wall. Moreover, important qualitative abnormalities of LDLs, potentially atherogenic, are observed in type 2 diabetic patients: small dense, triglyceride-rich, LDL particles (known as subclass B), oxidized LDL and glycated LDL. All these qualitative modification of LDLs amplify the atherosclerotic process. Plasma high density lipoprotein (HDL) cholesterol is decreased in type 2 diabetes related to increased catabolism of HDL particles. One of the mechanism responsible for increased catabolism of HDLs is hypertriglyceridemia, promoting through cholesteryl ester transfer protein (CETP) the transfer of triglycerides (TG) to HDL leading to the formation of TG-rich HDLs which are very good substrates for hepatic lipase, enzyme in charge of HDLs catabolism. The reduction in plasma adiponectin level, observed in type 2 diabetes may be another mechanism involved in the diminution of HDL cholesterol. Furthermore, qualitative abnormalities of HDLs are described in type 2 diabetes: enrichment in triglycerides and glycation, which may impair HDL-mediated cholesterol efflux and reverse cholesterol transport. In addition to their role in reverse cholesterol transport, HDLs usually show antioxidative, anti-inflammatory, anti-thrombotic and endothelium-dependent vasorelaxant effects. It has been shown that HDLs from patients with type 2 diabetes have a significant reduction in their antioxidative and endothelium-dependent vasorelaxant properties.
 ...
PMID:Lipid modification in type 2 diabetes: the role of LDL and HDL. 1965 Aug 52

The aim of the study was to test whether fasting or postprandial cholesteryl ester transfer protein (CETP) concentrations are associated with postprandial changes in high-density lipoprotein cholesterol (HDL-c) concentrations after fat-rich or carbohydrate-rich meals. Postmenopausal women (76 with normal glucose metabolism [NGM], 41 with type 2 diabetes mellitus [T2DM], and 38 T2DM women with statin therapy [T2DM-ST]) received 2 consecutive fat-rich or carbohydrate-rich meals on separate occasions. Linear regression analysis was performed to assess the associations of fasting CETP and postprandial changes of CETP with postprandial changes in HDL-c. Mean plasma HDL-c concentrations decreased significantly after the fat-rich meals: 0.18 +/- 0.09 mmol/L in NGM, 0.16 +/- 0.09 mmol/L in T2DM, and 0.14 +/- 0.08 mmol/L in T2DM-ST women. This effect was smaller after using carbohydrate-rich meals: 0.12 +/- 0.09 mmol/L in the NGM, 0.12 +/- 0.08 mmol/L in the T2DM, and 0.10 +/- 0.05 mmol/L in the T2DM-ST study group. Higher fasting but not postprandial CETP concentrations were associated with a larger postprandial decrease in HDL-c (beta -0.034; 95% confidence interval, -0.067 to -0.001) after the fat-rich meals. This association was independent of the postprandial increase in triglycerides and similar among the 3 study groups. A high fasting CETP concentration may contribute to the postprandial atherogenic lipoprotein profile in postmenopausal women by decreasing HDL-c after fat-rich meals. This effect is independent from the postprandial increase in triglycerides.
 ...
PMID:Fasting cholesteryl ester transfer protein concentration is independently associated with the postprandial decrease in high-density lipoprotein cholesterol concentration after fat-rich meals: the Hoorn prandial study. 2000 42

The common TaqIB variant in the gene coding for cholesteryl ester transfer protein (CETP), a key enzyme in reverse cholesterol transport, has been associated with higher HDL-C levels and with a more atheroprotective HDL subpopulations profile. Similar information are lacking in women with diabetes. The effect of menopause and the CETP polymorphism on lipid, lipoprotein profile, as well as on apoA-I-containing HDL subclasses distribution, as determined by two-dimensional gel electrophoresis, was examined in a group of women with and without type 2 diabetes. Diabetic women showed a less atheroprotective lipid and HDL subpopulations profile, with lower levels of the large alpha-1 (P=0.006), alpha-2 (P=0.005), and prealpha-1 (P=0.02), and higher concentration of the small alpha-3 HDL particles (P=0.02) as compared to controls, independently from menopause, HDL-C and triglycerides concentrations. CETP TaqIB genotype distribution was in the Hardy-Weinberg equilibrium and comparable in the two groups, but the effect of CETP polymorphism was limited to diabetic women. In this group, the CETP variant showed significant interactions with HOMA(IR) (P<0.001), BMI (P<0.001), and triglycerides (P<0.00001), with significantly higher HDL-C levels and a more protective HDL subpopulations profile in B2 allele carriers with lower HOMA(IR), BMI or triglycerides levels. At multivariate analysis, CETP polymorphism, apoA-I, triglycerides and BMI were independent determinants of HDL-C concentration in diabetic women; apo-A-I, triglycerides, age and creatinine in controls. Type 2 diabetes is associated with a more atherogenic lipid profile; the CETP TaqIB variant may partly prevent these modifications in diabetic women with a milder degree of insulin resistance and its related disorders.
 ...
PMID:Influence of menopause and cholesteryl ester transfer protein (CETP) TaqIB polymorphism on lipid profile and HDL subpopulations distribution in women with and without type 2 diabetes. 2000 32

Insulin resistance and type 2 diabetes are associated with low HDL-cholesterol (HDL-c) levels, which would impair reverse cholesterol transport (RCT). A promising therapeutic strategy is to raise HDL with cholesteryl ester transfer protein (CETP) inhibitors, but their effects on RCT remains to be demonstrated in vivo. We therefore evaluated the effects of CETP inhibitor torcetrapib in CETP-apolipoprotein (apo)B100 mice made obese and insulin resistant with a 60% high-fat diet. High-fat diet over 3 months increased body weight and homeostasis model of insulin resistance index by 30% and 846%, respectively (p < 0.01 for both vs. chow-fed mice). Total cholesterol (TC) increased by 46% and HDL-c/TC ratio decreased by 28% (both p < 0.05). Compared to vehicle, high-fat-fed mice treated with torcetrapib (30 mg/kg/day, 3 weeks) showed increased HDL-c levels and HDL-c/TC ratio by 41% and 37% (both p < 0.05). Torcetrapib increased in vitro macrophage cholesterol efflux by 22% and in vivo RCT through a 118% increase in (3) H-bile acids fecal excretion after (3) H-cholesterol labeled macrophage injection (p < 0.01 for both). Fecal total bile acids mass was also increased by 158% (p < 0.001). In conclusion, CETP inhibition by torcetrapib improves RCT in CETP-apoB100 mice. These results emphasize the potential of CETP inhibition to prevent cardiovascular diseases.
 ...
PMID:CETP inhibitor torcetrapib promotes reverse cholesterol transport in obese insulin-resistant CETP-ApoB100 transgenic mice. 2221 22

A low plasma level of HDL cholesterol is an atherosclerotic risk factor; however, emerging evidence suggests that low HDL levels might also contribute to the pathophysiology of type 2 diabetes mellitus (T2DM) through direct effects on plasma glucose. In the past decade, animal and clinical studies have uncovered a previously undescribed spectrum of HDL actions, indicating that HDL may control glucose homeostasis through mechanisms including insulin secretion, direct glucose uptake by muscle via the AMP-activated protein kinase, and possibly enhanced insulin sensitivity. These effects are mediated by multiple cell types via mechanisms including preservation of cell function through cellular lipid removal and also via direct signaling events. We suggest a paradigm shift from HDL being a bystander to being an active player in diabetic pathophysiology, which raises the possibility that HDL elevation could be a novel therapeutic avenue for T2DM. The entry of HDL-raising agents of the cholesteryl ester transfer protein (CETP) inhibitor class into late-phase clinical trials creates potential for rapid clinical translation. This Review will discuss the emerging evidence for a role of HDL-mediated glucose regulation in the pathophysiology of T2DM, and will also outline the therapeutic potential for HDL elevation for the prevention and management of T2DM.
 ...
PMID:The emerging role of HDL in glucose metabolism. 2227 Nov 88

This review of the exercise genomics literature emphasizes the highest quality articles published in 2011. Given this emphasis on the best publications, only a small number of published articles are reviewed. One study found that physical activity levels were significantly lower in patients with mitochondrial DNA mutations compared with controls. A two-stage fine-mapping follow-up of a previous linkage peak found strong associations between sequence variation in the activin A receptor, type-1B (ACVRIB) gene and knee extensor strength, with rs2854464 emerging as the most promising candidate polymorphism. The association of higher muscular strength with the rs2854464 A allele was confirmed in two separate cohorts. A study using a combination of transcriptomic and genomic data identified a comprehensive map of the transcriptomic features important for aerobic exercise training-induced improvements in maximal oxygen consumption, but no genetic variants derived from candidate transcripts were associated with trainability. A large-scale de novo meta-analysis confirmed that the effect of sequence variation in the fat mass and obesity-associated (FTO) gene on the risk of obesity differs between sedentary and physically active adults. Evidence for gene-physical activity interactions on type 2 diabetes risk was found in two separate studies. A large study of women found that physical activity modified the effect of polymorphisms in the lipoprotein lipase (LPL), hepatic lipase (LIPC), and cholesteryl ester transfer protein (CETP) genes, identified in previous genome-wide association study reports, on HDL cholesterol. We conclude that a strong exercise genomics corpus of evidence would not only translate into powerful genomic predictors but also have a major effect on exercise biology and exercise behavior research.
 ...
PMID:Advances in exercise, fitness, and performance genomics in 2011. 2233 29

To address the effects of ezetimibe on high-density lipoprotein (HDL) metabolism, the HDL subclasses, cholesteryl ester transfer protein (CETP), and lecithin-cholesterol acyltransferase (LCAT) were measured in patients with type 2 diabetes mellitus (T2DM). Twenty-three hypercholesterolemic patients with T2DM were treated with 10 mg of ezetimibe daily for 12 weeks. Plasma total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol (C), HDL-C, HDL(2)-C, HDL(3)-C, CETP mass, and LCAT activity were measured. HDL-C and HDL(2)-C increased by 5% (p<0.05) and 12% (p<0.01), respectively, in response to ezetimibe. Of the 23 patients, 21 had decreased CETP mass, which led to an average reduction of 20% (p<0.0001). LCAT activity also decreased by 6% (p<0.01). A significant positive correlation was found in the changes from baseline between HDL(2)-C and CETP mass, whereas a significant inverse relationship was observed between HDL(3)-C and CETP mass. Furthermore, the change in HDL-C was positively correlated with the change in LCAT activity. In conclusion, ezetimibe may affect HDL metabolism and reverse cholesterol transport, especially CETP, in T2DM. These observations may provide some insights into how ezetimibe prevents atherosclerosis.
 ...
PMID:Ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein, decreases cholesteryl ester transfer protein in type 2 diabetes mellitus. 2285 Jan 30

Cardiovascular disease (CVD) is a significant cause of death in Europe. In addition to patients with proven CVD, those with type 2 diabetes (T2D) are at a particularly high-risk of CVD and associated mortality. Treatment for dyslipidaemia, a principal risk factor for CVD, remains a healthcare priority; evidence supports the reduction of low-density lipoprotein cholesterol (LDL-C) as the primary objective of dyslipidaemia management. While statins are the treatment of choice for lowering LDL-C in the majority of patients, including those with T2D, many patients retain a high CVD risk despite achieving the recommended LDL-C targets with statins. This 'residual risk' is mainly due to elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. Following statin therapy optimisation additional pharmacotherapy should be considered as part of a multifaceted approach to risk reduction. Fibrates (especially fenofibrate) are the principal agents recommended for add-on therapy to treat elevated TG or low HDL-C levels. Currently, the strongest evidence of benefit is for the addition of fenofibrate to statin treatment in high-risk patients with T2D and dyslipidaemia. An alternative approach is the addition of agents to reduce LDL-C beyond the levels attainable with statin monotherapy. Here, addition of fibrates and niacin to statin therapy is discussed, and novel approaches being developed for HDL-C and TG management, including cholesteryl ester transfer protein inhibitors, Apo A-1 analogues, mipomersen, lomitapide and monoclonal antibodies against PCSK9, are reviewed.
...
PMID:Managing the residual cardiovascular disease risk associated with HDL-cholesterol and triglycerides in statin-treated patients: a clinical update. 2393 1

High-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles transport cholesterol in plasma and play an important role in cellular cholesterol homeostasis, which influences cell function. The risk of coronary artery disease (CAD) associated with high levels of LDL-cholesterol (LDL-C) can be reduced by treatment with statins, which reduce LDL-C levels by inhibiting cellular cholesterol synthesis. However, patients who are treated with high doses of statins, especially secondary CAD prevention, regardless of their resulting LDL-C levels, are still at high risk of CAD. Therefore, there has been growing interest in HDL-directed therapies. Inhibitors of cholesteryl ester transfer protein (CETP) substantially increase HDL-C levels (by 31-138%). However, it is still unclear whether or not CETP inhibitors can reduce the risk of CAD associated with low HDL-C levels, while reconstituted HDL or apolipoprotein A-I mimetic peptides increase the functionality of HDL. Low levels of HDL-C are often complicated with metabolic disorders, including hypertriglyceridemia, metabolic syndrome, and type 2 diabetes mellitus, and lifestyle changes are effective for correcting these conditions. Physical activity and exercise training increase HDL-C levels, especially HDL2-C levels, by multiple mechanisms. Therefore, although using HDL-directed therapies that increase HDL-C levels and/or improve the function of HDL is a reasonable approach for reducing the residual risk of CAD as a complement to LDL-C-lowering therapy, lifestyle modifications including exercise to improve metabolic disorders should be considered as the first option.
 ...
PMID:Therapeutic approaches to the regulation of metabolism of high-density lipoprotein. Novel HDL-directed pharmacological intervention and exercise. 2410 98


<< Previous 1 2 3 4 5 6 Next >>